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Pulsed low-dose RANKL as a potential therapeutic for postmenopausal osteoporosis
Anna Cline-Smith, … , Zachary S. Buchwald, Rajeev Aurora
Anna Cline-Smith, … , Zachary S. Buchwald, Rajeev Aurora
Published August 18, 2016
Citation Information: JCI Insight. 2016;1(13):e88839. https://doi.org/10.1172/jci.insight.88839.
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Research Article Bone biology Inflammation

Pulsed low-dose RANKL as a potential therapeutic for postmenopausal osteoporosis

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Abstract

A number of studies in model animal systems and in the clinic have established that RANKL promotes bone resorption. Paradoxically, we found that pulsing ovariectomized mice with low-dose RANKL suppressed bone resorption, decreased the levels of proinflammatory effector T cells and led to increased bone mass. This effect of RANKL is mediated through the induction of FoxP3+CD25+ regulatory CD8+ T cells (TcREG) by osteoclasts. Here, we show that pulses of low-dose RANKL are needed to induce TcREG, as continuous infusion of identical doses of RANKL by pump did not induce TcREG. We also show that low-dose RANKL can induce TcREG at 2, 3, 6, and 10 weeks after ovariectomy. Our results show that low-dose RANKL treatment in ovariectomized mice is optimal at once-per-month doses to maintain the bone mass. Finally, we found that treatment of ovariectomized mice with the Cathepsin K inhibitor odanacatib also blocked TcREG induction by low-dose RANKL. We interpret this result to indicate that antigens presented to CD8+ T cells by osteoclasts are derived from the bone protein matrix because Cathepsin K degrades collagen in the bone. Taken together, our studies provide a basis for using low-dose RANKL as a potential therapeutic for postmenopausal osteoporosis.

Authors

Anna Cline-Smith, Jesse Gibbs, Elena Shashkova, Zachary S. Buchwald, Rajeev Aurora

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Figure 1

Pulsed RANKL is required for the bone anabolic effect of low-dose RANKL.

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Pulsed RANKL is required for the bone anabolic effect of low-dose RANKL....
Twelve-week-old C57BL/6J mice were either sham-operated or OVX using pumps or pulsed with low-dose RANKL. Two weeks after surgery, ALZET pumps were implanted in the i.p. cavity that contained either PBS or RANKL. All groups were pulsed with PBS or with an equivalent dose of RANKL (0.125 mg/kg, pulsed twice 24 hours apart) as indicated in the plots. (A) Flow cytometry shows that pulsed but not continuous exposure to RANKL induced TcREG. (B) Quantification of FACS data of TcREG levels across all groups (6–8 mice/group). (C) Consistent with TcREG induction, decrease in TEFF cells (gated on CD45+CD3+ cells, and then on CD44+) was only observed in mice pulsed with RANKL but not treated with RANKL delivered by pumps. (D) Decreased levels of bone resorption were observed in mice pulsed with low-dose RANKL but not in mice with continuous exposure to RANKL. Modestly higher (but statistically significant) levels of bone resorption were observed in mice treated with continuous RANKL. (E) Bone volume (BV/TV) decreased in mice where RANKL was delivered by pump but was restored to levels observed in sham-operated mice when pulsed with RANKL. (F) Consistent with serum CTX and BV/TV results, an increase in bone mineral density (BMD) was observed in mice treated with pulsed RANKL but decreased in mice where RANKL was delivered by pump. (G and H) Pulsed low-dose RANKL decreased osteoclast numbers. Quantitation of osteoclast numbers/mm bone (N.OC/BS) and osteoclast surface/bone surface (OC.S/BS) is shown in G, and representative images are shown in H from sham and ovariectomized mice treated with infused and pulsed RANKL. Arrowheads indicate Tartrate-resistant acid phosphatase–positive (TRAP+) cells. Data is from 6–8 mice per group. Group statistical significance was calculated using Mann-Whitney U test. ***P < 1 × 10−3; **P < 0.01; *P < 0.05.

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